Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) of unknown etiology characterized by chronic gastrointestinal (GI) tract inflammation. The key pathological mechanism in IBD may involve a dysregulated immune response to GI tract antigens or infections. Inflammatory Th1 responses characterized by interferon-gamma and tumor necrosis factor-alpha synthesis correlate with IBD, whereas Th2 responses characterized by interleukin-4 and transforming growth factor beta-1 synthesis correlate with protection from IBD. Susceptibility genes contribute to IBD, but inheriting these genes is not sufficient for disease development. Undefined environmental risk factors play a disease-determining role. We hypothesize that insufficient sunlight for vitamin D biosynthesis is an environmental risk factor for IBD. We propose to use the hormonally active vitamin D metabolite, 1,25-dihydroxy vitamin D3 to inhibit IBD development and to treat established IBD in murine models of IBD as a first step in developing a novel therapeutic strategy for this incurable disease. PROPOSED COMMERCIAL APPLICATION: Incurable IBD afflicts two million individuals and costs about $1.2 billion annually to treat. The steroids, immunosuppressants and surgical treatments for IBD symptoms have undesireable side-effects. An FDA-approved short-term treatment (mouse-human IgG1 monoclonal antibody to tumor necrosis factors- alpha) has projected annual sales of $100 million. The commercial potential of a long-term vitamin D-based therapeutic might be greater than $100-150 million.